Assessment of the impact of implementation research on the Visceral Leishmaniasis (VL) elimination efforts in Nepal

Nepal, Bangladesh, and India signed a Memorandum of Understanding (MoU) in 2005 to eliminate visceral leishmaniasis (VL) as a public health problem from the Indian subcontinent by 2015. By 2021, the number of reported VL cases in these countries had declined by over 95% compared to 2007. This dramatic success was achieved through an elimination programme that implemented early case detection and effective treatment, vector control, disease surveillance, community participation, and operational research that underpinned these strategies. The experience offered an opportunity to assess the contribution of implementation research (IR) to VL elimination in Nepal. Desk review and a stakeholder workshop was conducted to analyse the relationship between key research outputs, major strategic decisions in the national VL elimination programme, and annual number of reported new cases over time between 2005 and 2023. The results indicated that the key decisions across the strategic elements, throughout the course of the elimination programme (such as on the most appropriate tools for diganostics and treatment, and on best strategies for case finding and vector management), were IR informed. IR itself responded dynamically to changes that resulted from interventions, addressing new questions that emerged from the field. Close collaboration between researchers, programme managers, and implementers in priority setting, design, conduct, and review of studies facilitated uptake of evidence into policy and programmatic activities. VL case numbers in Nepal are now reduced by 90% compared to 2005. Although direct attribution of disease decline to research outputs is difficult to establish, the Nepal experience demonstrates that IR can be a critical enabler for disease elimination. The lessons can potentially inform IR strategies in other countries with diseases targeted for elimination.

Nepal signed a Memorandum of Understanding (MoU) with Bangladesh and India in 2005 to eliminate VL as a public health problem from the region by 2015 [12].By 2021, the number of reported VL cases in these countries had declined by over 95% compared to 2007 [13].The target of the MoU was to achieve disease elimination (new case rate < 1/10,000 population at the district level) by 2015, through 3 phases of preparatory (2005 to 2008), attack (2008 to 2015), and consolidation (2015 onwards).The 5 strategic elements for elimination were early case diagnosis and complete treatment, integrated vector management (IVM), effective disease surveillance, social mobilization and partnership, and operational research.
The UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization (WHO), and several other partners have coordinated and financed implementation research (IR) in support of the VL elimination initiative in the Indian subcontinent before and throughout the course of the regional elimination programme.Available data on IR in the Indian subcontinent with a particular focus on Nepal, which covered all strategic elements and sustained throughout the course of the programme, may provide useful insight from the national perspective on the contribution of IR to achieving disease elimination targets.
The objective of the review is to describe and analyse key characteristics, contributions, milestones, and impact of IR on the elimination of VL as a public health problem in Nepal.

Methodology
A desk review of relevant VL publications, documents on VL elimination, and strategies and operational plans of Nepal or relevant to Nepal (from internal and external sources) was conducted.
Expert consultations were held with key stakeholders including national VL programme managers, VL treating clinicians, entomologists, and researchers to collect information on implementation or operational research activities and alignment with the programme and IR needs to achieve sustainability of elimination.The consultations included national program officers and the WHO country office.
A 5-day workshop (23 to 27 September 2021) was organized with academic institutions, national programme managers, and development partners.The workshop discussed on the role and contributions of IR to the elimination effort so far and identified the research and programmatic priorities to achieve and maintain VL elimination going forward.The discussion points and recommendations of the workshop have been provided in findings and discussion sections below.

Findings
IR on VL in Nepal covered all the strategic elements of the Kala-Azar Elimination Programme.TDR-supported country-led IR established the burden of VL, characterized population healthseeking behaviour, investigated feasibility of new interventions, identified barriers to early diagnosis and treatment, developed strategies for cost-effective active case detection (ACD), demonstrated effective and long-lasting vector control interventions, explored environmental determinants (e.g., housing as a risk factor for VL transmission), and examined the role of frontline health workers.Based on the findings from these studies and other similar research, which also fed into regional consensus, the national VL elimination program developed strategies, guidelines, and implementation plans for the attack phase of VL elimination in line with the recommendations of the WHO regional technical advisory group (RTAG), within the context of the WHO-supported regional VL elimination strategy [14,15].
Key decisions underpinned by sustained IR that directly impacted on reduced case burden in Nepal included the following: (i) rK39-based rapid test employed as a confirmatory test for VL as of 2005, following extensive field validation; (ii) miltefosine (MIL) replaced sodium stibogluconate (SSG) as a first line of treatment in 2008 to 2014; (iii) liposomal amphotericin B (L-AmB) replaced MIL in 2015 in response to increased treatment failures and relapse rates; (iv) combination therapy was introduced in Nepal's national treatment protocol in 2014; (v) active case detection (ACD) was incorporated into the national VL elimination protocol; and (vi) integrated vector management (IVM) was recognized as an important element in the elimination efforts.

VL trends in Nepal 2002-2020
In 2003, Nepal witnessed the highest case load of VL, although there were many outbreaks of VL in the past [16].In the same year, the rotation of synthetic pyrethroids for vector management was introduced.The overall trend of VL cases decreased significantly thereafter.The number of cases and deaths has been steadily falling since the VL elimination initiative started in 2005 (Fig 1).In 2008, MIL was introduced as oral monotherapy.The number of cases decreased further in comparison to previous years.This could be due to the convenience of the oral medication influencing patient compliance to treatment.Around the same period in 2009, long-lasting insecticide-treated nets (LLINs) were introduced in addition to indoor residual spraying (IRS), two measures that helped decrease the man-vector contact and, thus, the VL burden in the country.In addition, ACD was introduced into the VL elimination program in 2014 after a series of large intervention studies to identify the most cost-effective way of ACD.Overall, the number of VL cases has decreased by 90% in 2020 as compared to 2002, which is most likely a result of the synergistic impact of all interventions of the VL elimination program.

Diagnostic tests for VL
The direct agglutination test (DAT) had been in use as a diagnostic tool for VL since the early 90s following its assessment through TDR-supported research, which had confirmed it to be specific and sensitive and relatively acceptable for field laboratory settings [17,18].In subsequent years, rK39-based rapid test was found to be more cost-effective and simpler to use in field settings [19][20][21][22][23][24].The heterogeneity in test results of rK39 could be due to geographic region, commercial brand, disease prevalence, sample size in the study, type of reference standard, and risk of bias during testing [25].The sensitivity of rK39 is 97% and specificity is 90.2% in Indian subcontinent, and because of ease of use [25], it was recommended for diagnosis of VL in Indian subcontinent.rK39 was introduced as a diagnostic tool in the national VL elimination program in Nepal in 2005.The key studies on VL diagnostics have been given in Table 1.

Treatment regimens for visceral leishmaniasis
SSG was first introduced in Nepal in 1982 and became a first-line choice for treatment of VL in 1994.The study conducted by Karki and colleagues [32] on SSG revealed satisfactory results demonstrating better efficacy in those treated for a longer period.However, SSG showed increasing failure rates of 10% to 30% in Nepal [33] and 65% in Bihar [34] at the turn of the century.Amphotericin B was introduced for the treatment of VL in 1994.Subsequently, a TDRsupported Phase IV trial of MIL [35] showed that it was a safe and effective oral drug for treatment of VL.Oral monotherapy with MIL was introduced in 2008 as a first-line drug for VL in the absence of contraindications, until revised in 2014.Following the introduction of MIL as a first-line regimen, TDR supported another Phase IV trial conducted by Banjara and colleagues [36] in Saptari district.Although MIL was relatively safer and easier to administer than SSG [37], it is potentially teratogenic and, hence, contraindicated in pregnancy and during breastfeeding.The study by Rijal and colleagues [38] reported a 10% to 20% relapse rate after treatment with MIL.Banjara and colleagues [36] and Uranw and colleagues [39] showed that poor adherence and insufficient dose were associated with the occurrence of relapses.On the other hand, MIL is, in some case, a useful drug as a rescue treatment for patients with VL relapse [40].TDR-supported trials conducted in the Indian subcontinent showed that combined therapies had a favourable outcome for VL treatment [41][42][43][44].These studies revealed that combined therapy reduces the dose requirements without compromising the cure rate.The national treatment protocol of 2014 introduced combined therapy as a second-line treatment for VL.The combination regimen consists of L-AmB (5 mg/kg, single infusion) plus 7 days MIL (50 mg 2 times a day or, alternatively, L-AmB (5 mg/kg, single infusion) plus 10 days paromomycin (PM) (11 mg/kg base) or MIL plus PM for 10 days.Combined therapy has replaced amphotericin B monotherapy as a second-line treatment shifting it to third-line treatment in the national guideline of 2019.
The TDR-supported dose finding studies conducted in India showed that L-AmB was safe, effective, and favorable for the treatment of VL with minimal toxicity [41,45].In 2014, L-AmB was introduced into the treatment protocol for VL and is, since 2015, the recommended firstline drug in the national guideline for VL elimination.
Table 2 presents the key studies on drugs for VL treatment.

VL vector control
Joshi and colleagues (2008), Joshi and colleagues (2009), and Das and colleagues (2010) [54,55,56] in their TDR-funded study found that integrated vector management (IVM) can play a vital role in the VL elimination program.This was subsequently introduced into the 2010 national guidelines for VL elimination.TDR-funded studies have found that indoor residual spraying (IRS), insecticide-treated nets (ITNs), and insecticidal wall painting (IWP) are effective ways to control sandflies in Nepal [57,58].IRS with DDT, Malathion, and Lambda Cyhalothrin (ICON) had been in use from 1992 until 2002 [59,60].From 2003 onwards, the rotational substitution of synthetic pyrethroids was introduced in order to avoid vector resistance.Alpha cypermethrin was used in 2003 and 2012, while Lambda Cyhalothrin was reintroduced in 2007.A Lambda cyhalothrin study funded by TDR showed 97% mean vector mortality and a beneficial impact of IRS for up to 4 weeks after insecticide spray [61].However, the substandard performance and management of the spraying activity increased the risk of insecticide resistance [60,62,63].The studies by Joshi and colleagues (2009), Picado and colleagues (2009), and Picado and colleagues (2010) [55,64,65] did not show a significant reduction of VL incidence after the use of LLINs, but the study by Das and colleagues (2010), Mondal and colleagues (2016), and Das and colleagues (2012) [56,58,66] found LLINs to be a favorable alternative to IRS.Key studies on vector control are shown in Table 3.

VL case detection and surveillance
Various TDR-funded studies have explored different models of ACD reaching a similar conclusion that ACD is a cost-effective approach and appropriate for the elimination program [16,[71][72][73][74]. Singh and colleagues [72], in their TDR-funded study, assessed different ACD strategies in order to identify the most cost-effective approach and periodicity of ACD.They showed that the "camp approach" (periodic fever camps with VL screening) is recommended for high VL endemic areas, the "index approach" (perifocal screening around a VL case) for high to moderate VL areas, and the "incentive approach" (payment of community health workers for each case detected) in low endemic areas.Banjara and colleagues [68] also emphasized the needed reinforcement of community health workers.One of the early TDR-funded studies conducted in rural Nepal had already highlighted the need for optimal engagement of the local health workers to encourage villagers to actively participate in the VL control program [75].In the recent TDR study by Lim and colleagues [76], it was found that the delay in case reporting from the first symptoms to start of appropriate treatment was 68 days in VL program districts and 83 days in non-program (new foci) districts.Similarly, the diagnostic delay for program and nonprogram districts was 38 and 36 days, respectively.In order to facilitate a responsive intervention, delivery of timely and reliable information towards awareness of VL and its prompt treatment is essential.Table 4 summarizes key studies on surveillance of VL.

Discussion
Nepal eliminated VL as a public health problem at the district level in 2014 and has sustained the status for 3 years [79].Evidence shows that transmission of Leishmania donovani in Nepal has decreased significantly during the elimination programme [31].Despite the recent emergence of new foci in some hilly districts requiring further exploration and intervention, the KA elimination programme in Nepal is a success story [31].This achievement is obviously an outcome of converging inputs from multiple health system blocks driving effective information systems, access to essential medicines, financing, and leadership/governance [80], including strong political commitment internally, as well as the advantages accruing from a regional approach (with successful reduction of disease burden during the same period in Bihar, India, bordering with Nepal).Key drivers of success that are frequently cited are interventions and tools such as rapid diagnosis with rK39 RDT, active case finding, treatment with L-AmB, and IRS [14].The research that underpins these tools and their implementation receives less attention.However, effective IR would be expected to have contributed to strategic decisions in the choice and implementation of the interventions and guided their implementation across these strategic elements.The impact of IR on disease burden is difficult to measure because it acts through downstream drivers limiting direct attribution.Long-term interventions such as the VL elimination programme where IR is integrated into the strategy offer opportunities to explore the contribution of IR to the achievement of public health targets.
One of the early research projects supported by TDR described peoples' knowledge, attitude, and practice regarding VL in rural Nepal.The data obtained from this study helped in planning and evaluating VL-related control activities.
The VL elimination program benefitted from successive innovations, which facilitated early diagnosis (field-friendly rapid confirmatory test), effective treatment (MIL, L-AmB), and ACD based on VL burden (camp, household, index-based) and effective vector control (LLINs, IRS).These measures were introduced at various stages in the course of the elimination programme following policy decisions at the national and regional levels based on evidence and the recommendations of the RTAG of WHO.The success of these interventions is evident in the rapid decline of reported cases and death over the years (Fig 1).Because IR lies behind these policy decisions, one can safely conclude that IR has contributed to reduction in disease burden, albeit indirectly through evidence uptake into policy.

Lessons and perspectives
The VL elimination program in the Indian subcontinent implemented a package of clearly defined evidence-based interventions and an effective performance management process.It could sustain partnerships that contributed in different ways and communicated well with the program.It benefitted from a strong political commitment.An important component among these key areas for public health program success that the program enjoyed was a research platform to develop the evidence base for action [81].
In addition to scientific publications, standard operating procedures (SOPs), policy briefs, monitoring and evaluation (M&E) handbooks, and other operational documents were developed by researchers and programme staff in collaboration with WHO, TDR, and national partners.These have largely been adopted by the national authorities.The input, together with findings generated through operational research supported by other development partners in these countries, has shaped the RTAG's recommendations and helped advance the VL elimination effort in Nepal (as in the other countries).Every year, TDR organizes joint meetings of program managers, country researchers, TDR, WHO/NTD, WHO-SEARO, RTAG, DNDi, McGill University, and other partners to update participants on the progress and challenges of the program as well as to share new IR findings, identify research priorities, and draft the proposals for the next research phase.Country researchers have participated in the development of national and regional strategic plans and programs.RTAG meeting recommendations were translated into the strategies for VL elimination in the country (Table 5).The lessons learned and the consistent documentation of the regional achievements could serve as reference for VL elimination in Africa.For Nepal to sustain progress towards the elimination goal, more efficient and effective methods for ACD and vector management, which respond to the changing epidemiological profile in the countries, are required.

Conclusions
The VL elimination strategy in Nepal provides a good example of the power of IR to facilitate disease elimination through an effective partnership of stakeholders with national disease programmes as part of a WHO regional effort.Investment by TDR and others in collaborative IR has led to a series of strategic decisions with significant impact on disease burden.This successful model of a sustained research-to-practice-to-research cycle, of country-led IR informing national decision, is rich with good practices that can potentially be replicated in other countries with diseases targeted for elimination or serve as case studies in implementation science.Top Five Papers